| Title: | Deficiency of Peptidylglycine-alpha-amidating Monooxygenase, a Cause of Sarcopenic Diabetes Mellitus |
| Journal: | The Journal of Clinical Endocrinology & Metabolism |
| Published: | 13 Aug 2024 |
| Pubmed: | https://pubmed.ncbi.nlm.nih.gov/39137152/ |
| DOI: | https://doi.org/10.1210/clinem/dgae510 |
Publication 13010
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Abstract
CONTEXT: Peptidylglycine-α-amidating monooxygenase (PAM) is a critical enzyme in the endocrine system responsible for activation, by amidation, of bioactive peptides.</p>
OBJECTIVE: To define the clinical phenotype of carriers of genetic mutations associated with impaired PAM-amidating activity (PAM-AMA).</p>
DESIGN: We used genetic and phenotypic data from cohort studies: the Malmö Diet and Cancer (MDC; 1991-1996; reexamination in 2002-2012), the Malmö Preventive Project (MPP; 2002-2006), and the UK Biobank (UKB; 2012).</p>
SETTING: Exome-wide association analysis was used to identify loss-of-function (LoF) variants associated with reduced PAM-AMA and subsequently used for association with the outcomes.</p>
PATIENTS OR OTHER PARTICIPANTS: This study included n∼4500 participants from a subcohort of the MDC (MDC-Cardiovascular cohort), n∼4500 from MPP, and n∼300,000 from UKB.</p>
MAIN OUTCOME MEASURES: Endocrine-metabolic traits suggested by prior literature, muscle mass, muscle function, and sarcopenia.</p>
RESULTS: Two LoF variants in the PAM gene, Ser539Trp (minor allele frequency: 0.7%) and Asp563Gly (5%), independently contributed to a decrease of 2.33 [95% confidence interval (CI): 2.52/2.15; P = 2.5E-140] and 0.98 (1.04/0.92; P = 1.12E-225) SD units of PAM-AMA, respectively. The cumulative effect of the LoF was associated with diabetes, reduced insulin secretion, and higher levels of GH and IGF-1. Moreover, carriers had reduced muscle mass and function, followed by a higher risk of sarcopenia. Indeed, the Ser539Trp mutation increased the risk of sarcopenia by 30% (odds ratio 1.31; 95% CI: 1.16/1.47; P = 9.8E-06), independently of age and diabetes.</p>
CONCLUSION: PAM-AMA genetic deficiency results in a prediabetic sarcopenic phenotype. Early identification of PAM LoF carriers would allow targeted exercise interventions and calls for novel therapies that restore enzymatic activity.</p>
12 Authors
- Alice Giontella
- Mikael Åkerlund
- Kevin Bronton
- Cristiano Fava
- Luca A Lotta
- Aris Baras
- John D Overton
- Marcus Jones
- Andreas Bergmann
- Paul Kaufmann
- Yulia Ilina
- Olle Melander
1 Application
| Application ID | Title |
|---|---|
| 76658 | Investigation of genetic variants associated with circulating levels of cardiometabolic biomarkers and outcomes. |
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